A comprehensive study of APOE and the noncoding RNA AANCR to advance Alzheimer’s Disease treatment

Brown University, Providence RI

Investigators

Abstract

PROJECT SUMMARY APOE4 is a major genetic risk factor for Alzheimer's Disease, which affects millions worldwide. In the United States, over 60% of Alzheimer's patients carry at least one APOE4 allele. Despite three decades of research, the absence of precision medicine targeting APOE4 remains a critical gap. Recent gene therapy breakthroughs, like mRNA vaccines and antisense oligonucleotide-based medicine, raise hope for APOE- focused Alzheimer's treatments. The APOE gene has three common alleles, E2, E3 and E4. APOE3 is the common allele, and it is not associated with susceptibility to Alzheimer’s Disease. APOE4 is the ancestral allele; although it is the susceptibility allele, its frequency has remained high suggesting potential selective advantages. APOE4 and APOE3 alleles are distinguished by a single base difference (C vs. T at SNP rs429358). APOE4 exhibits a dominant-like effect, elevating Alzheimer’s Disease risk in individuals with just one copy of the E4 allele. Even with intense searches for treatments, precision medicine for this devastating disease remains elusive. An incomplete understanding of the regulation of APOE expression and function may have contributed to this therapeutic gap. Precision therapeutics targeting APOE4 while minimizing side effects demand a comprehensive mechanistic understanding of APOE expression regulation and function. Our recent discovery of the enhancer RNA, APOE-activating noncoding RNA (AANCR) is a significant advance, shedding light on cell-type specific APOE expression and its stress responses. This discovery provides critical insights into APOE expression regulation and susceptibility to Alzheimer’s Disease. Our project aims to elucidate how AANCR regulates APOE transcription and how AANCR itself is modulated to maintain cell-type specific and stress-induced APOE expression. Notably, we observed APOE induction in the central nervous system during stress. To advance APOE- targeted interventions, understanding its stress-induced functions is imperative. In stress-activated astrocytes and microglia, we will assess how APOE expression and genotypes affect cellular function. Multiomic analyses will investigate cytokine levels, gene expression patterns, and lipid profiles to characterize the function of APOE. Subsequent co-culture experiments will assess the effects of APOE and these associated factors on neuronal health, including synaptic activity and survival. Leveraging our RNA, genetics, and neurobiology expertise, along with preliminary data, we are uniquely poised to address these critical knowledge gaps. Our project integrates a thorough understanding of APOE regulation in homeostasis and stress response with its broader implications on neuronal health. This dual focus is crucial for developing targeted, effective treatment for Alzheimer's Disease.